Therapeutic methods involving gastrointestinal implants

ABSTRACT

The present invention provides combination therapies for treating a metabolic disorder, such as type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)) in an individual undergoing treatment with a gastrointestinal implant. The combination therapies described herein include methods for treating an individual with a gastrointestinal implant with a metabolic agent, a bariatric procedure, and/or a microbiota modulator.

BACKGROUND OF THE INVENTION

According to the Center for Disease Control, over 10% of the populationof the United States has been diagnosed with type 2 diabetes or ispredicted to develop type 2 diabetes, over half of whom are clinicallyobese. Type 2 diabetes and obesity can be broadly characterized asmetabolic disorders, which often lead to life-threatening co-morbiditiesincluding non-alcoholic steatohepatitis (NASH), non-alcoholic fattyliver disease (NAFLD), hypertension, coronary artery disease,hypercholesteremia, sleep apnea, and pulmonary hypertension.

Patients suffering from metabolic diseases typically have an aberrantphysiological response to ingested food after a meal. In particular,inadequate secretion of insulin has been associated with development ofmetabolic disorders such as type 2 diabetes. This blunted insulinresponse is caused by a loss of the “incretin effect,” the gut-dependentsecretion of incretins (e.g., hormones such as glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)). Thus,the modulation of signaling pathways in the gastrointestinal tract isemerging as a promising approach for treating metabolic disorders, suchas type 2 diabetes, obesity, and related comorbidities.

Many conventional treatments involve surgical modification ofgastrointestinal anatomy. Such procedures include, for example, gastricremodeling and gastric bypass. Unfortunately, the morbidity rate forsurgical procedures is alarmingly high, with at least 11% of casesrequiring surgical intervention for correction. Early small bowelobstruction has been estimated to occur at a rate of between 2-6% inthese surgeries, and mortality rates are reported to be approximately0.5-1.5%. While invasive and irreversible surgery seems to be effectivewhen successfully performed, the associated complication rates areunacceptably high. Laparoscopic techniques adapted to these proceduresprovide fewer surgical complications but continue to expose thesepatients to high operative risk in addition to requiring an enormouslevel of skill by the surgeon.

To address these risks, non-surgical methods involving the implantationof temporary gastrointestinal devices can be implemented to treatmetabolic disorders (e.g., type 2 diabetes, obesity, and relatedcomorbidities (e.g., NASH or NAFLD)). Devices such as gastrointestinalsleeves can modulate key hormones involved in insulin sensitivity,glucose metabolism, satiety, and food intake. However, metabolicdisorders are complex diseases with multi-faceted etiologies, andindividuals undergoing treatment with temporary gastrointestinal devicesmay require additional medical interventions. Additionally, patientsoften suffer from various metabolic disorder-related comorbidities(e.g., non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liverdisease (NAFLD)). Thus, there is a need for combinatorial treatmentapproaches to support temporary gastrointestinal devices to providecomprehensive treatment strategies to individuals having metabolicdisorders, such as type 2 diabetes, obesity, or related comorbiditiesthereof, such as NASH or NAFLD.

SUMMARY OF THE INVENTION

The present invention is directed to combination therapies for treatinga metabolic disorder (e.g., type 2 diabetes, obesity, and relatedcomorbidities (e.g., NASH or NAFLD)) in an individual undergoingtreatment with a gastrointestinal implant.

In one aspect, the invention features a method for treating a metabolicdisorder (e.g., type 2 diabetes, obesity, and related comorbidities(e.g., NASH or NAFLD)) in an individual undergoing treatment with agastrointestinal implant, wherein the method includes administering oneor more metabolic agents to the individual in an amount and for aduration to treat the metabolic disorder (e.g., type 2 diabetes,obesity, and related comorbidities (e.g., NASH or NAFLD)).

In some embodiments, the one or more metabolic agents includes anincretin modulator. In some embodiments, the incretin modulator may be aglucagon-like peptide-1 (GLP-1) receptor agonist. The GLP-1 receptoragonist may be liraglutide, exenatide, lixisenatide, dulaglutide, oralbiglutide. The liraglutide can be administered at a dose from 0.006 mgto 3 mg. The exenatide can be administered at a dose from 0.05 μg to 10μg. The lixisenatide can be administered at a dose from 0.1 μg to 20 μg.The dulaglutide can be administered at a dose from 0.0075 mg to 1.5 mg.The albiglutide can be administered at a dose from 0.3 mg to 50 mg.

In some embodiments, the incretin modulator includes a dipeptidylpeptidase-4 (DPP-4) inhibitor. The DPP-4 inhibitor may be sitagliptin,saxagliptin, alogliptin, or linagliptin. The sitagliptin can beadministered at a dose from 0.25 mg to 100 mg. The saxagliptin can beadministered at a dose from 0.025 mg to 5 mg. The alogliptin can beadministered at a dose of 0.0625 mg to 25 mg. The linagliptin can beadministered at a dose of 0.025 mg to 5 mg.

In some embodiments, the one or more metabolic agents can beadministered by an enteral route. Alternatively, the one or moremetabolic agents can be administered by a parenteral route.

In some embodiments, the one or more metabolic agents can beadministered one or more times per month. In some embodiments, the oneor more metabolic agents can be administered one or more times per week.In some embodiments, the one or more metabolic agents can beadministered one or more times per day. In some embodiments, the one ormore metabolic agents can be administered prior to treatment with thegastrointestinal implant. In some embodiments, the one or more metabolicagents can be administered during treatment with the gastrointestinalimplant.

In a second aspect, the invention features a method for treating ametabolic disorder (e.g., type 2 diabetes, obesity, and relatedcomorbidities (e.g., NASH or NAFLD)) in an individual undergoingtreatment with a gastrointestinal implant, wherein the method includesone or more bariatric procedures to treat the metabolic disorder (e.g.,type 2 diabetes, obesity, and related comorbidities (e.g., NASH orNAFLD)).

In some embodiments, the one or more bariatric procedures comprises arestrictive bariatric procedure. In some embodiments, the restrictivebariatric procedure includes providing a space-occupying device to anindividual. For example, the space-occupying device can be anintragastric balloon. In some embodiments, the restrictive gastricprocedure includes a gastroplasty procedure. For example, thegastroplasty procedure can include placing transmural tissue anchorplications in the gastric fundus and body.

In some embodiments, the one or more bariatric procedures can beadministered prior to treatment with the gastrointestinal implant.Alternatively, the one or more bariatric procedures can be administeredduring treatment with the gastrointestinal implant.

In a third aspect, the invention features a method for treating ametabolic disorder (e.g., type 2 diabetes, obesity, and relatedcomorbidities (e.g., NASH or NAFLD)) in an individual undergoingtreatment with a gastrointestinal implant, wherein the method includesadministering one or more microbiota modulators to an individual in anamount and for a duration to treat a metabolic disorder (e.g., type 2diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)).

In some embodiments, the one or more gastrointestinal microbiotamodulators includes one or more species of bacteria. For example, thetreatment with one or more species of bacteria can be provided by afecal microbiota transplant.

In some embodiments, the one or more gastrointestinal microbiotamodulators includes a prescribed diet regimen. For example, theprescribed diet regimen can comprise a food enriched in one or morepolyphenols, saccharides, polysaccharides, peptides, polypeptides,lipids, or any combination thereof. Additionally or alternatively, theprescribed diet regimen can include a food enriched in one or morespecies of bacteria.

In some embodiments, the one or more gastrointestinal microbiotamodulators includes a dietary supplement. For example, the dietarysupplement can be a prebiotic supplement. Additionally or alternatively,the dietary supplement can be a probiotic supplement. The prebioticsupplement can include a polyphenol, saccharide, polysaccharide,peptide, polypeptide, lipid, or any combination thereof.

In some embodiments, the one or more gastrointestinal microbiotamodulators includes treatment with one or more bacteriophage.

In some embodiments, the one or more gastrointestinal microbiotamodulators is administered prior to treatment the gastrointestinalimplant. In some embodiments, the one or more gastrointestinalmicrobiota modulators is administered during treatment with thegastrointestinal implant.

In some embodiments, the one or more gastrointestinal microbiotamodulators can be administered by an enteral route. In some embodiments,the one or more gastrointestinal microbiota modulators can beadministered by a parenteral route.

In some embodiments, the one or more gastrointestinal microbiotamodulators modifies the composition, growth, or activity of thegastrointestinal microbiota of the individual.

In another aspect, the method includes providing a gastrointestinalimplant to the individual, wherein the implant comprises a sleeve, andrecommending (i) one or more bariatric procedures to treat a metabolicdisorder (e.g., type 2 diabetes, obesity, and related comorbidities(e.g., NASH or NAFLD)), (ii) administration of one or more metabolicagents in an amount and for a duration to treat the metabolic disorder(e.g., type 2 diabetes, obesity, and related comorbidities (e.g., NASHor NAFLD)), or (iii) administration of one or more microbiota modulatorsin an amount and for a duration to treat the metabolic disorder (e.g.,type 2 diabetes, obesity, and related comorbidities (e.g., NASH orNAFLD)).

In some embodiments of any of the preceding methods, the metabolicdisorder-related comorbidity may be type 2 diabetes, obesity, NASH, orNAFLD.

In some embodiments of any of the preceding methods, thegastrointestinal sleeve can be configured for implantation within agastrointestinal tract at or distal to a pylorus of the individual. Insome embodiments, the gastrointestinal sleeve comprises a wave anchor.For example, the wave anchor is a barbed wave anchor. In someembodiments, the wave anchor can be configured to reside distal to apylorus of the individual.

DETAILED DESCRIPTION OF THE INVENTION

As described herein, the invention provides treatment methods (e.g.,treatment with a metabolic agent, bariatric procedure, or microbiotamodulator) that can be used in an individual undergoing treatment with agastrointestinal implant. The methods of the invention may be used inthe treatment and/or prophylaxis of a metabolic disorder (e.g., type 2diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)).

As used herein, the term “bariatric surgery” or “bariatric procedure”refers to a procedure for weight loss involving modifications of thegastrointestinal tract and includes, but is not limited to proceduressuch as gastric banding, sleeve gastrectomy, GI bypass procedure (e.g.,roux-en-Y, biliary duodenal bypass, loop gastric bypass), treatment withan intragastric balloon or other space-occupying devices,gastroplasties, aspiration therapy, endoscopic enteral anastomosis, andbiliopancreatic diversion. “Endoscopic bariatric surgery” refers to anybariatric procedures associated with the use of an endoscope (e.g., aflexible tube that may include additional tools directly or indirectlyassociated with the tube) inserted through small incisions or naturalbody openings. As used herein, the term “gastroplasty” refers tosurgical procedures that modify the stomach or other parts of the GItract. For example, gastroplasty can be used to change the shape or sizeof the stomach. Subtypes of gastroplasty include bariatric gastroplasty,such as vertical banded gastroplasty, silicone ring verticalgastroplasty, horizontal banded gastroplasty, vertical bandedgastroplasty, endoscopic sleeve gastroplasty with an overstitchendoscopic suturing device, and primary obesity surgery endolumenal.

As used herein, the term “comorbidity” or “related comorbidity” refersto one or more conditions, syndromes, diseases, or disorders thatco-occur with metabolic disorders and can be either directly orindirectly linked to metabolic disorders. For example, metabolicdisorder-related conditions may include type 2 diabetes, obesity,non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis(NASH), dyslipidemia, elevated serum/plasma LDL, elevated VLDL, elevatedtriglycerides, elevated cholesterol, plaque formation leading tonarrowing or blockage of blood vessels, glucose intolerance, myocardialinfarction, increased risk of hypertension/stroke, or coronary heartdisease. As used herein, “diabetes mellitus type 2” or “type 2 diabetes”(also known as diabetes mellitus type 2, non-insulin-dependent diabetes(NIDDM), obesity-related diabetes, or adult-onset diabetes) refers to ametabolic disorder that is primarily characterized by insulinresistance, relative insulin deficiency, and hyperglycemia.

As used herein, an “effective amount” or “therapeutically effectiveamount” are used interchangeably to refer to an amount of an agent(e.g., metabolic agent or microbial modulating agent) that allows it totreat or prevent, partially or totally, type 2 diabetes, obesity, andrelated comorbidities (e.g., NASH or NAFLD)), as described herein. Aneffective amount of an agent may therefore induce a reduction in a bloodsugar level and/or a loss of body weight. The effective amount willdepend upon a number of factors, including biological activity, age,body weight, sex, general health, severity of the condition to betreated, as well as appropriate pharmacokinetic properties. Atherapeutically effective amount of a composition of the presentinvention can be administered by an appropriate route in a single doseor multiple doses. Further, the dosages of the composition can beproportionally increased or decreased as indicated by the exigencies ofthe therapeutic or prophylactic situation.

As used herein, the term “gastrointestinal,” “GI,” “gastrointestinaltract,” or “GI tract” refer to the entire alimentary canal, includingfrom the mouth to the anus, and individual portions thereof, such as theesophagus, stomach, small intestine, large intestine, and rectum.

As used herein, the term “gastrointestinal implant” includes an anchorfor securely positioning the device to the stomach and a sleeve to limitabsorption of nutrients in the duodenum. A “sleeve,” as used herein,refers to a hollow, cylindrical liner that is open at both ends andadapted to extend at least into the duodenum. Partially digested food,or chyme, passing through the GI tract passes through the interior ofthe sleeve. When implanted in an intestine, the sleeve may accomplishone or more of the following: limit the digestion or absorption ofnutrients; delay the mixing of chyme with digestive enzymes; providenegative feedback; reduce hormone triggers; and treat diseases, such asmetabolic disorders (e.g., type 2 diabetes, obesity, and relatedcomorbidities (e.g., NASH or NAFLD)). A portion of the sleeve iscomprised of a “flexible” material meaning that the material isconformable to collapse in the intestine to a small volume.

As used herein, the term “incretin” refers to a compound that directlyor indirectly stimulates insulin release, inhibits glucagon release, andreduces gastric emptying. For example, incretins stimulate an increasein the amount of insulin released from the pancreas when plasma glucoselevels are elevated relative to normal after food consumption, therebyleading to a decrease in blood glucose levels. Specific examples ofincretins include gastric inhibitory peptide (i.e., glucose-dependentinsulinotropic polypeptide, or GIP) and glucagon-like peptide-1 (GLP-1),along with their analogs and derivatives.

The term “metabolic agent” as used herein refers to any natural orsynthetic substance that is therapeutically effective in the treatmentor prevention of metabolic disorders (e.g., type 2 diabetes, obesity,and related comorbidities (e.g., NASH or NAFLD)) in an individualundergoing treatment with a gastrointestinal implant. Metabolic agentsinclude “incretin modulators”, which include i) agents that function asincretins (e.g., GLP-1 or GIP) or incretin mimetics (e.g., GLP-1receptor agonists) and ii) agents that function as enhancers of theincretin response (e.g., dipeptidyl peptidase IV (DPP-4) inhibitors).Incretin modulators increase insulin secretion, decrease gastricemptying, and decrease blood glucose levels, and are thus useful in thetreatment of disorders characterized by hyperglycemia (e.g., type 2diabetes). The term “GLP-1 receptor agonist” or “GLP-1 agonist” as usedherein refers to a substance (e.g., peptides or small molecules) thatactivate a GLP-1 receptor, such as the human GLP-1 receptor. Forexample, peptides that activate the human GLP-1 receptor (e.g., nativeGLP-1 peptide hormones GLP-1(7-37), GLP-1(7-36)amide, oxyntomodulin,exendin-3, exendin-4, glucagon, gastric inhibitory polypeptide (GIP),functional peptide analogues and derivatives thereof) as well ascompounds that function similarly (e.g., exenatide, liraglutide,lixisenatide, albiglutide, dulaglutide, taspoglutide, and semaglutide).The term “dipeptidyl peptidase-4 inhibitor”, as used herein, refers to acompound that exhibits inhibitory activity on the enzyme dipeptidylpeptidase IV (DPP-4), thus acting as an incretin enhancer, and includescompounds such as sitagliptin, vildagliptin, saxagliptin, linagliptin,gemiliptin, anagliptin, teneligliptin, alogliptin, trelagliptin,dutogliptin, omarigliptin, berberine, and lupeol. Other metabolic agentsuseful as part of the invention include metformin, sodium-glucoseco-transporter 2 (SGLT-2) inhibitors (e.g., empagliflozi, canagliflozin,or dapagliflozin), sulfonylureas (e.g., glimepiride, glyburide,glipizide, glyburide, tolazamide, or tolbutamide), thiazolidinedione,and insulin.

As used herein, “restrictive gastric surgery” refers to a type ofbariatric surgery that modifies the GI tract in a manner that limits theamount of a food that can be consumed and/or increases the likelihood ofsatiety by reducing the volume of free space available in the stomach orother parts of the GI tract (e.g., through use of a space-occupyingdevice or by directly modifying the gastrointestinal tract). As usedherein, a “space-occupying device” refers to a device that can be usedin a restrictive gastric surgery to limit gastric capacity (e.g., reducethe volume of free space available in the stomach or other parts of theGI tract).

As used herein, the term “treatment” refers to clinical intervention inan attempt to alter the natural course of the individual being treated,and can be performed either for prophylaxis or during the course ofclinical pathology. Desirable effects of treatment include, but are notlimited to, preventing occurrence or recurrence of disease, alleviationof symptoms, diminishment of any direct or indirect pathologicalconsequences of the disease, decreasing the rate of disease progression,amelioration or palliation of the disease state, and improved prognosis.In some embodiments, the gastrointestinal implant is used to controlmetabolic disorders (e.g., type 2 diabetes, obesity, and relatedcomorbidities (e.g., NASH or NAFLD)). In some embodiments, removal ofgastrointestinal implant or administration of antibiotics is provided todelay development of a disease or to slow the progression of a disease.

As used herein, the term “microbiota” refers to the community ofmicroorganisms that occur (sustainably or transiently) in and on ananimal subject, typically a mammal such as a human, and includeseukaryotes, archaea, bacteria, fungi, and viruses (including bacterialviruses i.e., phage). By “gastrointestinal microbiota” or “GImicrobiota” is meant any microbiota associated with (e.g., in or on) oneor more portions of the GI tract, including indigenous or transientmicrobes. As used herein, the term “fecal microbiota” refers tomicroorganisms that are present in the gut, intestine, colon, and/orfeces of a normal healthy adult human. By “fecal microbiota transplant”is meant the transfer of stool from a healthy donor into thegastrointestinal tract of a different individual for treatment orprophylactic purposes via any route of administration (e.g., viacolonoscopy, naso-enteric tube, capsules.

As used herein, a “prebiotic” refers to a substance (e.g., a syntheticor natural substance in a food, a supplement, or a pharmaceuticalcomposition) that selectively promotes the growth of beneficial bacteriaor inhibits the growth or mucosal adhesion of pathogenic bacteria in thegastrointestinal tract. Prebiotics may be fermented or metabolized bythe gastrointestinal microflora and/or by probiotics. For example,prebiotics can include mucopolysaccharides, oligosaccharides,polysaccharides, amino acids, vitamins, nutrient precursors andproteins. Additional non-limiting examples of prebiotics include acaciagum, alpha glucan, arabinogalactans, beta glucan, dextrans,fructooligosaccharides, fucosyllactose, galactooligosaccharides,galactomannans, gentiooligosaccharides, glucooligosaccharides, guar gum,inulin, isomaltooligosaccharides, lactoneotetraose, lactosucrose,lactulose, levan, maltodextrins, milk oligosaccharides, partiallyhydrolyzed guar gum, pecticoligosaccharides, resistant starches,retrograded starch, sialooligosaccharides, sialyllactose,soyoligosaccharides, sugar alcohols, xylooligosaccharides, or theirhydrolysates, or combinations thereof.

As used herein, the terms “probiotic” and “probiotic micro-organisms”are used interchangeably to refer to food-grade microorganisms (e.g.,alive, including semi-viable or weakened, and/or non-replicatingmicroorganisms), microbial cell preparations, or components of microbialcells that could confer health benefits on the host when administered inadequate amounts, more specifically, that beneficially affect a host byimproving its intestinal microbial balance, leading to effects on thehealth or well-being of the host. In general, it is believed that thesemicro-organisms inhibit or influence the growth and/or metabolism ofpathogenic bacteria in the intestinal tract. The probiotics may alsoactivate the immune function of the host. For this reason, there havebeen many different approaches to include probiotics into food products.Non-limiting examples of probiotics include Aerococcus, Aspergillus,Bacillus, Bacteroides, Bifidobacterium, Candida, Clostridium,Debaromyces, Enterococcus, Fusobacterium, Lactobacillus, Lactococcus,Leuconostoc, Melissococcus, Micrococcus, Mucor, Oenococcus, Pediococcus,Penicillium, Peptostrepococcus, Pichia, Propionibacterium,Pseudocatenulatum, Rhizopus, Saccharomyces, Staphylococcus,Streptococcus, Torulopsis, Weissella, or combinations thereof.

By “subject” or “patient” is meant any animal, e.g., a mammal (e.g., ahuman). A subject who is being treated for a metabolic disorder, e.g.,high blood sugar, diabetes (e.g., type 2 diabetes), obesity, NASH,NAFLD, or a related comorbidity thereof, is one who has been diagnosedby a medical or veterinary practitioner as the case may be as havingsuch a condition. Diagnosis may be performed by any suitable means.Subjects of the invention may have been subjected to standard tests ormay have been identified, without examination, as one at high risk ofhaving or developing a metabolic disorder, e.g., type 2 diabetes,obesity, NASH, NAFLD, or a related comorbidity due to the presence ofone or more risk factors, such as age, genetics, or family history.

I. Treatment Indications

As described herein, the invention provides treatment methods (e.g.,treatment with a metabolic agent, bariatric procedure, or microbiotamodulator) that can be used in an individual undergoing treatment with agastrointestinal implant. The methods of the invention may be used inthe treatment and/or prophylaxis of a metabolic disorder (e.g., type 2diabetes, obesity, and related comorbidities (e.g., NASH, NAFLD, highblood pressure, high cholesterol, and sleep apnea)). For example,related conditions may include disorders including NASH, NAFLD, highblood pressure, high cholesterol, sleep apnea, dyslipidemia,hyperglycemic conditions (e.g., prediabetes, insulin-independent type 2diabetes) or physiological conditions or disorders associated thereof.Hyperglycemic conditions treatable by a method of the invention can alsoinclude a histopathological change associated with chronic or acutehyperglycemia (e.g., degeneration of pancreas (beta.-cell destruction),kidney tubule calcification, degeneration of liver, eye damage (diabeticretinopathy), diabetic foot, ulcerations in mucosa such as mouth andgums, excess bleeding, delayed blood coagulation, or wound healing).Disorders treatable also include, for example, abnormally elevatedserum/plasma LDL, VLDL, triglycerides, cholesterol, plaque formationleading to narrowing or blockage of blood vessels, glucose intolerance,myocardial infarction, increased risk of hypertension/stroke, orcoronary heart disease.

II. Gastrointestinal Implants

As described herein, the invention provides therapies (e.g., treatmentwith a metabolic agent, bariatric procedure, or microbiota modulator) tobe used in an individual undergoing treatment with a gastrointestinalimplant. For example, the gastrointestinal implant can include a sleevethat limits intestinal nutrient absorption. Such gastrointestinalsleeves are known in the art and include those described in U.S. Pat.Nos. 7,267,694, 7,608,114, 7,695,446, 7,678,068, 8,486,153, 7,476,256,7,815,589, 7,766,973, and 7,976,488. Alternatively, gastrointestinalimplants featuring restrictive elements can be used to increase satietyby limiting flow of ingested material (e.g., chyme) through thegastrointestinal tract. Such implants include those described in U.S.Pat. Nos. 7,771,382, 8,920,358, and 7,819,836.

The invention may involve gastrointestinal implants anchored by anymethod. In some instances, the sleeve may be anchored bytissue-penetrating features, such as barbs or blunt elements (e.g.,loops, helices, etc.) that integrate within a gastrointestinal lumen,including, but not limited to, those described in U.S. Pat. Nos.9,265,596 and 8,834,553. Other tissue-penetrating features that may beuseful for, e.g., anchoring a gastrointestinal device in an individual'sgastrointestinal tract include, e.g., sutures, staples, or the like.Alternatively, gastrointestinal implants may not include a tissuepenetrating feature and may instead be atraumatically positioned withina gastrointestinal tract. Such atraumatic gastrointestinal implantsinclude, but are not limited to, those described in U.S. Pat. Nos.5,830,584, 7,122,058, 9,278,019, 8,211,186, 8,475,401, 8,109,895,8,568,488, 7,931,693, 9,060,835, 8,636,683, 8,821,429, 8,048,169, andU.S. Publication Numbers US2014/0296770A1, US2015/0190259A1,US2011/0190905A1, and US2012/0095384A1.

Gastrointestinal implants of the invention can be positioned anywhere inthe gastrointestinal tract. In some cases, the implant is anchoreddistal to the pylorus (e.g., in the duodenum, e.g., at the duodenalbulb, or at or distal to the ampulla of Vader). In other cases, thegastrointestinal implant is anchored at the pylorus (e.g., supported byelements on both proximal and distal sides of the pyloric sphincter).Alternatively, the implant may be substantially positioned within thestomach (e.g., within the antrum or body of the stomach, e.g., to occupyspace in the stomach).

III. Combination Therapies with Metabolic Agents

Provided herein are methods of treating a metabolic disorders (e.g.,type 2 diabetes, obesity, and related comorbidities (e.g., NASH orNAFLD)), wherein an individual undergoing treatment with agastrointestinal implant is also treated with a metabolic agent. Themetabolic agent in the method of the inventions can be any suitablemetabolic agent known in the art or described herein. In some instances,the metabolic agent is an incretin modulator. Incretin modulators thatcan be used include, for example, glucagon-like peptide-1 (GLP-1)receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1receptor agonists that can be used include, but are not limited to,liraglutide (NN2211, sold under the brand names VICTOZA® and SAXENDA®),exenatide (sold under the brand names BYETTA®, BYDUREON®, and AMYLIN®),lixisenatide (sold under the brand names LYXUMIA® and ADLYXIN®),dulaglutide (sold under the brand name TRULICITY®), or albiglutide (soldunder the brand names EPERZAN® and TANZEUM®), and pharmaceuticallyacceptable salts thereof. DPP-4 inhibitors that can be used include, butare not limited to, sitagliptin (MK-0431, sold under the brand nameJANUVIA®, JANUMET®, JANUMET XR®, and JUVISYNC®), saxagliptin (sold underthe brand name ONGLYZA® and KOMBIGLYZE XR®), alogliptin (sold under thebrand names NESINA®, VIPIDIA®, KAZANO®, OSENI®, VIPIDOMET® (alogliptinin combination with metformin), and INCRESYNC® (alogliptin incombination with pioglitazone), linagliptin (sold under the brand namesTRADJENTA®, GLYXAMBI®, JENTADUETO®, and JENTADUETO XR®), andpharmaceutically acceptable salts thereof.

The metabolic agent of the invention may be administered in anypharmaceutically acceptable formulation containing the metabolic agentand any pharmaceutically acceptable diluents, carriers, or excipientsthat are nontoxic to recipients at the dosages and concentrationsemployed. Acceptable carriers and excipients may include buffers such asphosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acidand methionine, preservatives such as hexamethonium chloride,octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkoniumchloride, proteins such as human serum albumin, gelatin, dextran, andimmunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone,amino acids such as glycine, glutamine, histidine, and lysine, andcarbohydrates such as glucose, mannose, sucrose, and sorbitol. Thecompositions may be formulated according to conventional pharmaceuticalpractice. The concentration of the compound in the formulation will varydepending upon a number of factors, including the dosage of the drug tobe administered, and the route of administration.

Administration and Formulations

The methods described herein can be used in any therapeutic orprophylactic context in which the metabolic agent may be useful to theindividual undergoing treatment with a gastrointestinal implant. In someinstances, the metabolic agent (e.g., GLP-1 receptor agonist or DPP-4inhibitor) can be administered before, concurrently with, and/or aftertreatment with the gastrointestinal implant (e.g., before, during orafter implantation). For example, the metabolic agent (e.g., GLP-1receptor agonist or DPP-4 inhibitor) can be administered first followedby implantation of the gastrointestinal device. Alternatively, thegastrointestinal device can be implanted first, followed byadministration of the metabolic agent.

In accordance with the methods disclosed herein, the metabolic agent(e.g., GLP-1 receptor agonist or DPP-4 inhibitor) may be provided in anypharmaceutically acceptable formulation and administered in any mannerknown in the art which renders the metabolic agent biologicallyavailable to the subject or sample in effective amounts. The metabolicagent or a pharmaceutical composition including the metabolic agent maybe formulated for, e.g., oral administration, intravenousadministration, intramuscular administration, intradermaladministration, intraarterial administration, topical administration,intravaginal administration, subcutaneous administration, or byinhalation.

In some instances, the metabolic agent (e.g., GLP-1 receptor agonist orDPP-4 inhibitor) of the present invention may be formulated in the formof liquid solutions or suspensions and administered by any parenteralroute. Parenteral administration may include but is not limited tointravenous, intra-arterial, intradermal, subcutaneous, intramuscular,intracranial, intraorbital, ophthalmic, intraventricular, intracapsular,intraspinal, intracisternal, or intraperitoneal routes ofadministration. Pharmaceutical compositions for injection can beformulated using a sterile solution or any pharmaceutically acceptableliquid as a vehicle. Pharmaceutically acceptable vehicles include, butare not limited to, sterile water, physiological saline, or cell culturemedia (e.g., Dulbecco's Modified Eagle Medium (DMEM), α-Modified EaglesMedium (α-MEM), F-12 medium). For injectable formulations, variouseffective pharmaceutical carriers are known in the art (See, e.g.,Remington: The Science and Practice of Pharmacy, 22nd ed., (2012) andASHP Handbook on Injectable Drugs, 18th ed., 2014).

In some instances, the metabolic agent (e.g., GLP-1 receptor agonist orDPP-4 inhibitor) of the present invention may be formulated foradministration by any enteral route (e.g., orally). In some instances,the metabolic agent (e.g., GLP-1 receptor agonist or DPP-4 inhibitor)can be prepared in the form of an oral formulation. Formulations fororal use can include tablets, caplets, capsules, syrups, or oral liquiddosage forms containing the active ingredient(s) in a mixture withnon-toxic pharmaceutically acceptable excipients. These excipients maybe, for example, inert diluents or fillers (e.g., sucrose, sorbitol,sugar, mannitol, microcrystalline cellulose, starches including potatostarch, calcium carbonate, sodium chloride, lactose, calcium phosphate,calcium sulfate, or sodium phosphate); granulating and disintegratingagents (e.g., cellulose derivatives including microcrystallinecellulose, starches including potato starch, croscarmellose sodium,alginates, or alginic acid); binding agents (e.g., sucrose, glucose,sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch,pregelatinized starch, microcrystalline cellulose, magnesium aluminumsilicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, bufferingagents, and the like. Formulations for oral use may also be provided inunit dosage form as chewable tablets, non-chewable tablets, caplets,capsules (e.g., as hard gelatin capsules wherein the active ingredientis mixed with an inert solid diluent, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium).

Dosage

The dosage of the metabolic agent (e.g., GLP-1 agonist or DPP-4inhibitor) described herein depends on factors including the route ofadministration, the disease to be treated, and physical characteristics,e.g., age, weight, general health, of the subject (e.g., a human). Thedosage may be adapted by the physician in accordance with conventionalfactors such as the extent of the disease and different parameters ofthe subject. Typically, the amount of a metabolic agent (e.g. GLP-1agonist or DPP-4 inhibitor) contained within one or more doses may be anamount that effectively reduces the risk of or treats a metabolicdisorders (e.g., type 2 diabetes, obesity, and related comorbidities(e.g., NASH or NAFLD)) in a subject without inducing significanttoxicity.

In some instances, the metabolic agent is liraglutide orpharmaceutically acceptable salts thereof (NN2211, sold under the brandnames VICTOZA® and SAXENDA®) administered subcutaneously in doses fromabout 0.006 mg to about 3 mg (e.g., 0.012±0.006 mg, 0.024±0.012 mg,0.050±0.0.025 mg, 0.075±0.025 mg, 0.1±0.05 mg, 0.15±0.05 mg, 0.2±0.1 mg,0.4±0.2 mg, 0.6±0.4 mg, 1±0.5 mg, 1.5±0.5 mg, 2±0.5 mg, or 2.5±0.5 mg).In some instances, the metabolic agent is exenatide or pharmaceuticallyacceptable salts thereof (sold under the brand names BYETTA®, BYDUREON®,and AMYLIN®) administered subcutaneously in doses from about 0.05 μg toabout 3 μg (e.g., 0.05±0.01, 0.06±0.02 μg, 0.08±0.04 μg, 0.10±0.05 μg,0.15±0.05 μg, 0.2±0.1 μg, 0.4±0.2 μg, 0.6±0.2 μg, 0.8±0.2 μg, 1±0.5 μg,1.5±0.5 μg, 2±1 μg, 3±1 μg, 4±2 μg, 6±2 μg, or 8±2 μg). In someinstances, the metabolic agent is lixisenatide or pharmaceuticallyacceptable salts thereof (sold under the brand names LYXUMIA® andADLYXIN®) administered subcutaneously in doses from about 0.1 μg toabout 20 μg (e.g., 0.15±0.05 μg, 0.2±0.1 μg, 0.4±0.2 μg, 0.6±0.2 μg,0.8±0.2 μg, 1±0.5 μg, 1.5±0.5 μg, 2±1 μg, 3±1 μg, 4±2 μg, 6±2 μg, 8±2μg, 10±2 μg, 12±2 μg, 14±2 μg, 16±2 μg, or 18±2 μg). In some instances,the metabolic agent is dulaglutide or pharmaceutically acceptable saltsthereof (sold under the brand name TRULICITY®) administeredsubcutaneously in doses from about 0.008 mg to about 1.5 mg (e.g.,0.016±0.008 mg, 0.024±0.008 mg, 0.050±0.0.025 mg, 0.075±0.025 mg,0.1±0.05 mg, 0.15±0.05 mg, 0.2±0.1 mg, 0.4±0.2 mg, 0.6±0.4 mg, 1±0.5 mg,1.5±0.5 mg, 2±0.5 mg, or 2.5±0.5 mg). In some instances, the metabolicagent is albiglutide or pharmaceutically acceptable salts thereof (soldunder the brand names EPERZAN® and TANZEUM®) administered subcutaneouslyin doses from about 0.3 mg to about 50 mg (e.g., 0.5±0.2 mg, 0.7±0.2 mg,0.9±0.2 mg, 1±0.5 mg, 1.5±0.5 mg, 2±0.5 mg, 2.5±0.5 mg, 3±2 mg, 4±2 mg,6±2 mg, 8±2 mg, 10±2 mg, 12±2 mg, 14±2 mg, 16±2 mg, 18±2 mg, 20±5 mg,25±5 mg, 30±5 mg, 35±5 mg, 40±5 mg, or 45±5 mg).

In some instances, the metabolic agent is sitagliptin orpharmaceutically acceptable salts thereof (MK-0431, sold under the brandname JANUVIA®, JANUMET®, JANUMET XR 200 , and JUVISYNC®) orallyadministered in doses from about 0.25 mg to about 100 mg (e.g., 0.5±0.25mg, 0.75±0.25 mg, 1±0.5 mg, 1.5±0.5 mg, 2±0.5 mg, 2.5±0.5 mg, 3±2 mg,4±2 mg, 6±2 mg, 8±2 mg, 10±2 mg, 12±2 mg, 14±2 mg, 16±2 mg, 18±2 mg,20±5 mg, 25±5 mg, 30±5 mg, 35±5 mg, 40±5 mg, 45±5 mg, 50±10 mg, 60±10mg, 70±10 mg, 80±10 mg, or 90±10 mg). In some instances, the metabolicagent is saxagliptin or pharmaceutically acceptable salts thereof (soldunder the brand name ONGLYZA®, KOMBIGLZE XR®) orally administered indoses of about 0.025 mg to about 5 mg (e.g., 0.5±0.25 mg, 0.75±0.25 mg,1±0.25 mg, 1.5±0.5 mg, 2±0.5 mg, 2.5±0.5 mg, 3±0.5 mg, 3.5±0.5 mg, 4±0.5mg, or 4.5±0.5 mg). In some instances, the metabolic agent is alogliptinor pharmaceutically acceptable salts thereof (sold under the brand namesNESINA®, VIPIDIA®, KAZANO®, OSENI®, VIPIDOMET® (alogliptin incombination with metformin), and INCRESYNC® (alogliptin in combinationwith pioglitazone)) orally administered in doses of about 0.06 mg toabout 25 mg (e.g., 0.05±0.01 mg, 0.06±0.02 mg, 0.08±0.04 mg, 0.10±0.05mg, 0.15±0.05 mg, 0.2±0.05 mg, 0.25±0.05 mg, 0.5±0.05 mg, 0.35±0.5 mg,0.4±0.2 mg, 0.6±0.2 mg, 0.8±0.2 mg, 1±0.5 mg, 1.5±0.5 mg, 2±1 mg, 3±1mg, 4±2 mg, 6±2 mg, 8±2 mg, 10±2 mg, 15±5 mg, or 20±5 mg). In someinstances, the metabolic agent is linagliptin or pharmaceuticallyacceptable salts thereof (sold under the brand names TRADJENTA®,GLYXAMBI®, JENTADUETO®, and JENTADUETO XR®) orally administered in dosesof about 0.025 mg to about 5 mg (e.g., 0.5±0.25 mg, 0.75±0.25 mg,0.5±0.0.2 mg, 0.6±0.2 mg, 0.8±0.2 mg, 1±0.5 mg, 1.5±0.5 mg, 2±0.5 mg,2.5±0.5 mg, 3±0.5 mg, 3.5±0.5 mg, 4±0.5 mg, or 4.5±0.5 mg).

Any pharmaceutically acceptable formulation of the metabolic agent ofthe present invention can be administered one or more times per day(e.g., 1, 2, 3, or 4 times per day), one or more times per week (e.g.,1, 2, 3, 4, 5, or 6 days a week), or one or more times per month (e.g.,1, 2, or 3 weeks per month). The formulations can be administered to asubject in therapeutically effective amounts. The preferred dosage ofdrug to be administered is likely to depend on variables such as thetype and extent of the disorder, the overall health status of theparticular subject, the specific compound being administered, theexcipients used to formulate the compound, and its route ofadministration. Single or multiple administrations of the metabolicagent of the invention including an effective amount can be carried outwith dose levels and patterns being selected by the treating physician.The dose and administration schedule can be determined and adjustedbased on the severity of the disease or condition in the subject, whichmay be monitored throughout the course of treatment according to themethods commonly practiced by clinicians or those described herein. Thecompounds of the present invention may be used in combination with otherconventional methods of treatment (e.g., in combination with metformin)or therapy or may be used separately from conventional methods oftreatment or therapy.

IV. Combination Therapies with Bariatric Procedures Bariatric Procedures

Provided herein are methods of treating metabolic disorders (e.g., type2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)),wherein an individual undergoing treatment with a gastrointestinalimplant is treated with one or more bariatric procedures. Bariatricprocedures refer to procedures that modify the function, size, and/orshape of the gastrointestinal tract including, but not limited to,gastric banding, sleeve gastrectomy, GI bypass procedures (e.g.,roux-en-Y, biliary duodenal bypass, loop gastric bypass), intragastricballoon, vertical banded, gastroplasty, and biliopancreatic diversion.

In some instances, the bariatric procedure is a restrictive bariatricprocedure. For example, the restrictive bariatric procedure can restrictspace in the gastrointestinal tract indirectly (e.g., by providing aspace-occupying device) or directly (e.g., by modifying the shape and/orsize of the stomach). In some instances, the restrictive bariatricprocedure can provide an intragastric balloon as a space-occupyingdevice. Alternatively, the restrictive bariatric procedure can be agastroplasty procedure that modifies the size or shape of the stomach.For example, the gastroplasty procedure can involve the placement oftransmural tissue anchor plications in the gastric fundus and body(e.g., USGI® Primary Obesity Surgery Endolumenal (POSE) or otherprocedures using the USGI® Incisionless Operating Platform). In someinstances, the bariatric procedure can be performed on the same day thatthe gastrointestinal sleeve is implanted in the subject (e.g., within 15min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, or 12 hr, 24 hr before or afterimplantation). Alternatively, the bariatric procedure can be performedon a different day before or after the implantation of thegastrointestinal sleeve (e.g., within 36 hr, 2 days, 3 days, 4, days, 5days, 1 weeks, 2, weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months,5 months, or 6 months before or after implantation).

V. Combination Therapies with Microbiota Modulators

Provided herein are methods of treating metabolic disorders (e.g., type2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)),wherein an individual undergoing treatment with a gastrointestinalimplant is also treated with an agent that modulates the microbiota ofthe individual (e.g., an agent that increases the presence or activityof beneficial bacteria and/or suppresses the presence or activity ofpathogenic bacteria). As described herein, the microbiota modulator caninclude microbial agents (e.g., bacterial or fungal cells,bacteriophage, probiotics), non-microbial agents (e.g., compounds,pharmaceutical substances, prebiotics), or a combination thereof. Forexample, the treatment can include administration of (i) one or moremicro-organisms, (ii) one or more compounds or agents, such asprebiotics that foster the growth, survival, persistence, transit orexistence of microbiota, or a combination thereof. The microbiotamodulator composition may alternatively or additionally comprise aselective microbial growth inhibitor. The microbiota modulator mayalter, for example, the diversity, composition, or abundance (e.g.,increase or decrease the relative level) of microbiota in thegastrointestinal tract of the subject, wherein the level of beneficialbacteria is increased and/or the level of harmful bacteria is reduced.In particular, the microbiota modulator may alter the gastrointestinalmicrobiota in in such a manner that leads to synergistic health benefitfor the individual, such as greater weight loss or improved bloodglucose levels, than when the individual is treated with thegastrointestinal implant alone or the microbiota modulator alone.

The microbiota modulator can be administered at any time that benefitsthe subject during treatment with the gastrointestinal implant (e.g.,before, during, or after implantation). The microbiota modulator canalter microbiota in the subject to achieve a diversity, composition, orabundance of microbiota that is beneficial to the individual in thecontext of treating metabolic disorders (e.g., type 2 diabetes, obesity,and related comorbidities (e.g., NASH or NAFLD)). In one particularexample, the microbiota modulator can alter the microbiota of therecipient to make it similar (e.g., 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, or 100% similar) that of a healthy individual (e.g., anindividual without metabolic disorders (e.g., type 2 diabetes, obesity,and related comorbidities (e.g., NASH or NAFLD)). Alternatively, themicrobiota modulator can alter the microbiota of the recipient to makeit similar (e.g., 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or100% similar) to that of a subject who is responsive to a bariatricprocedure).

Microbial Agents (e.g., Probiotics)

The microbiota modulator composition may include one or more microbialstrains. Such microbial strains could be bacterial and fall within thescope of what is typically considered in the art to be a probiotic. Themicrobiota modulator composition may alternatively or additionallycomprise a growth medium for one or more microbial strains (e.g.,strains already present in the individual or included as part ofmicrobiota modulator composition). Microbial agents can include wholebacterial or fungal cells (e.g., viable (live) cells, dormant cells(e.g., endospores), inactivated cells, dead cells, or any combinationthereof) or substances that support (e.g., promote growth, diversity, ormaintenance of) a beneficial level or composition of microbiota in thegastrointestinal tract of a subject undergoing treat with agastrointestinal implant. The microbial cells may be derived frommicrobial populations (e.g., one or more phyla, genera, species, orstrains) found in nature (e.g., in a mammalian gastrointestinal tract)or derived from strains of bacteria not typically found in nature (e.g.,laboratory strains). The bacterial cells can contain a single phylum,genus, or species of bacteria or, alternatively, multiple phyla, genera,or species of bacteria. The bacteria that can be used in the treatmentmethods (e.g., bacteria common to the gut, colon or intestine) include,but are not limited to, bacterial phyla such as Bacteroidetes,Proteobacteria, Firmicutes, Tenericutes and Verrucomicrobia; bacterialclasses such as Mollicutes; bacterial orders such as Bacteroidales,Enterobacteriales, Erysipelotrichales, Clostridialel andVerrucomicrobiales; bacterial genera such as Alistipes, Escherichia,Clostridium, Allobaculum, and Akkermansia; or a combination thereof.

A microbial agent (e.g., bacterial or fungal cells) can be administeredin a probiotic formulation that includes, for example, food-grademicroorganisms (e.g., viable, semi-viable or weakened, and/ornon-replicating fungi or bacteria), metabolites, microbial cellpreparations or components of microbial cells that could confer healthbenefits on the host subject when administered in adequate amounts, morespecifically, that beneficially affect a host by improving itsintestinal microbial balance, leading to effects on the health orwell-being of the host (e.g., treatment of metabolic disorders (e.g.,type 2 diabetes, obesity, and related comorbidities (e.g., NASH orNAFLD))). The probiotic organism can be formulated in anytherapeutically effective formulation, e.g., for treating metabolicdisorders (e.g., type 2 diabetes, obesity, and related comorbidities(e.g., NASH or NAFLD)) and administered by any therapeutically effectiveroute (e.g., oral or rectal), including any of those described above(See section III of detailed description). For example, the probioticcan be administered as part of a supplement or pharmaceuticalcomposition. For example, the probiotic can be formulated as a culturein water or another liquid or semisolid medium in which the probioticremains viable; or as a freeze-dried powder containing the probioticorganism. Alternatively, the probiotic-containing composition can be aliquid or semi-solid food. For example, the probiotic-containingcomposition is a dairy or non-dairy food. In yet other embodiments, theprobiotic-containing composition is yogurt, butter, cheese, infantformula, or ice cream.

In some instances, food grade bacteria or fungi can be selected from thegroup consisting of Bifidobacterium, Lactobacillus, Lactococcus,Enterococcus, Streptococcus Ascomycota, Deuteromycota, Debaryomyces,Kluyveromyces, Saccharomyces, Yarrowia, Zygosaccharomyces, Candida, andRhodotorula; preferentially lactic acid bacteria and bifidobacteria, ormixtures thereof; and/or in particular may be selected from the groupconsisting of Bifidobacterium longum, Bifidobacterium lactis,Bifidobacterium animalis, Bifidobacterium breve, Bifidobacteriuminfantis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillussalivarius, Lactococcus lactis, Lactobacillus reuteri, Lactobacillusrhamnosus, Lactobacillus paracasei, Lactobacillus johnsonii,Lactobacillus plantarum, Lactobacillus salivarius, Enterococcus faecium,Saccharomyces cerevisia, Saccharomyces boulardii and Lactobacillusreuteri or mixtures thereof, preferably selected from the groupconsisting of Lactobacillus johnsonii, Bifidobacterium longum,Bifidobacterium longum, Bifidobacterium lactis, Lactobacillus paracasei,Lactobacillus rhamnosus GG, Lactobacillus rhamnosus, and mixturesthereof. Non-limiting examples of probiotics include Aerococcus,Aspergillus, Bacillus, Bacteroides, Clostridium, Fusobacterium,Leuconostoc, Melissococcus, Micrococcus, Mucor, Oenococcus, Pediococcus,Penicillium, Peptostrepococcus, Pichia, Propionibacterium,Pseudocatenulatum, Rhizopus, Staphylococcus, Streptococcus, Torulopsis,Weissella, or a combination thereof.

Fecal Microbiota Transplant

The microbiota modulator described herein can comprise whole bacterialcells supplied via a fecal sample or isolate thereof (e.g., a fecalsample containing an active bacterial population and/or substances tosupport said population). The fecal sample or isolate thereof can beprovided in the form of a fecal microbiota transplant, wherein the fecalmatter is taken from a donor and given to a recipient undergoingtreatment with the gastrointestinal implant. The donor can be a healthyindividual (e.g., a person who does not have metabolic disorders (e.g.,type 2 diabetes, obesity, and related comorbidities (e.g., NASH orNAFLD))). Alternatively, the fecal transplant donor can be anyindividual with a composition of gastrointestinal microbiota that may bebeneficial for the recipient (e.g., a subject undergoing treatment witha gastrointestinal implant). For example, the donor can be a subject whois or was previously responsive to a bariatric procedure. The microbiotamodulator can alter microbiota in the recipient to mimic or make itsimilar to microbiota found in the donor, such as a subject that isresponsive to a surgical procedure like gastric bypass or othergastrointestinal bariatric or metabolic procedures. In some instances,the existing microbiota of the recipient does not need to be clearedprior to administration of microbiota modulator. Alternatively,clearance of the existing microbiota of the recipient microbiota may benecessary. Methods for clearance of existing microbiota are known in theart. In one example, clearance can be accomplished by administering acocktail of antibiotics for one week until a day prior to the fecalmicrobiota transplant (e.g., metronidazole (1000 mg twice daily),rifaximin (550 mg twice daily), vancomycin (500 mg twice daily), andneomycin (1000 mg twice daily)).

Non-Microbial Agents (e.g., Prebiotics)

The microbiota modulator described herein can include one or moreprebiotics. The prebiotic can be a substance (e.g., a synthetic ornatural substance in a food, a supplement, or a pharmaceuticalcomposition) that selectively promotes the growth of beneficial bacteriaor inhibits the growth or mucosal adhesion of pathogenic bacteria in thegastrointestinal tract. Prebiotics may be fermented or metabolized bythe gastrointestinal microflora and/or by probiotics. Further, theadministration of one or more prebiotic compounds may selectivelyenhance the relative abundance or growth of one or more targetedmicrobiota.

The prebiotic in the methods of the invention can include, but is notlimited to, polyphenols, saccharides, mucopolysaccharides,oligosaccharides, polysaccharides, amino acids, peptides, polypeptides,lipids, vitamins, or nutrient precursors. Additional non-limitingexamples of prebiotics include acacia gum, alpha glucan,arabinogalactans, beta glucan, dextrans, fructooligosaccharides,fucosyllactose, galactooligosaccharides, galactomannans,gentiooligosaccharides, glucooligosaccharides, guar gum, inulin,isomaltooligosaccharides, lactoneotetraose, lactosucrose, lactulose,levan, maltodextrins, milk oligosaccharides, partially hydrolyzed guargum, pecticoligosaccharides, resistant starches, retrograded starch,sialooligosaccharides, sialyllactose, soyoligosaccharides, sugaralcohols, xylooligosaccharides, or their hydrolysates, or combinationsthereof. Other examples of prebiotics can include bacterial cell wallcomponents such as peptidoglycans, bacterial nucleic acids such as DNAand RNA, bacterial membrane components, and bacterial structuralcomponents such as proteins, carbohydrates, lipids and combinations ofthese such as lipoproteins, glycolipids and glycoproteins. Additionalexamples can also include organic acids, inorganic acids, bases,proteins and peptides, enzymes and co-enzymes, amino acids and nucleicacids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids,vitamins, bioactive compounds, metabolites containing an inorganiccomponent, small molecules, for example nitrous molecules or moleculescontaining a sulphurous acid, resistant starch, potato starch or highamylose starch, modified starches (including carboxylated starches,acetylated, propionated, and butyrated starches), non-digestibleoligosaccharides such as fructooligosaccharides. Prebiotics also includedietary fibers.

Administration

The microbiota modulator described herein may be formulated andadministered by any therapeutically effective or pharmaceuticallyacceptable methods known in the art (e.g., see section III of detaileddescription). Specifically, the microbiota modulator may be administeredby any method suitable for depositing in the gastrointestinal tract asubject (e.g., in an oral supplement or in food). Examples of routes ofadministration include, but are not limited to, rectal administration(e.g., by suppository, enema, upper endoscopy, upper push enteroscopy,or colonoscopy), intubation through the nose or the mouth (e.g., bynasogastric tube, nasoenteric tube, or nasal jejunal tube), or oraladministration (e.g., by a solid such as a pill, tablet, or capsule, orby liquid). Oral compositions may include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, thecomposition can be incorporated with any pharmaceutically acceptableexcipients and used in the form of tablets, or capsules, e.g., gelatincapsules. Oral compositions can also be prepared by combining acomposition with a food. In one embodiment a food used foradministration is chilled, for instance, ice cream or milk. Otheringredients may be added to a formulation to provide desiredcharacteristics such as flow, compression, hardness, and taste.

EXAMPLES Example 1. Use of a Metabolic Agent in a Subject UndergoingTreatment with a Gastrointestinal Implant

An individual with type 2 diabetes is undergoing treatment with agastrointestinal implant. The individual has a body mass index (BMI)>30mg/m² at the initiation of treatment. The individual fails to achieve areduction in weight, HbA1c, blood and/or urine glucose during the first3 months of treatment. In the presence of gastrointestinal implant,individual is administered the GLP-1 agonist, liraglutide. Liraglutideis given at an effective dose of 1.2 mg daily. After 9 months ofcombination therapy consisting of gastrointestinal implant plusliraglutide, individual attains >2.0% reduction in HbA1c, >10 kg loss ofweight, >10.0% reduction in total body weight, and improvements inglucose control. The combination of gastrointestinal implant andliraglutide is found to be superior to gastrointestinal implant orliraglutide alone.

Example 2. Restrictive Bariatric Surgery in a Subject UndergoingTreatment with a Gastrointestinal Implant

An individual with type 2 diabetes has a body mass index (BMI)>35 mg/m².The individual is recommended for therapy with a gastrointestinalimplant and space-occupying device (e.g., a device that displace volumesand induces gastric distention, but may also alter gastrointestinalmotility, nutrient transit, and hormone levels). The gastrointestinalimplant is delivered according to methods known in the art. Thespace-occupying device is delivered into the patients stomach eitherconcurrently with or separately from the gastrointestinal implant. Oncea patient has improved in blood glucose levels and lost the desiredamount of weight, or if efficacy plateaus, or if patient safety iscompromised, the inflated expandable member is deflated and removed bydisconnecting a tether (for concurrent delivery) prior to removal.Gastrointestinal implant can be removed or remain in place for furthertreatment. The combination of gastrointestinal implant andspace-occupying device is found to be superior to gastrointestinalimplant or space-occupying device alone.

Example 3. Gastroplasty Surgery in a Subject Undergoing Treatment with aGastrointestinal Implant

A restrictive procedure is performed on an individual to remodel thestomach via suturing, stapling, or tissue anchor placement to reducegastric volume or bypass an absorptive surface of the small intestine.The individual is recommended for therapy with a gastrointestinalimplant. The gastrointestinal implant is delivered according toconventional methods known in the art or concurrent with the restrictiveprocedure (i.e. tissue anchor placement with endoscope). The combinationof gastrointestinal implant and restrictive procedure facilitatesdurable weight loss and comorbidity improvement compared togastrointestinal implant or restrictive procedure alone.

Example 4. Fecal Microbiota Transplant in a Subject Undergoing Treatmentwith a Gastrointestinal Implant

An individual with type 2 diabetes is undergoing treatment with agastrointestinal implant. A fecal transplant is recommended tosupplement normalization of blood glucose levels and weight loss. Aportion of the patient's microbiome is sequenced and may be used todetect the presence or absence of specific candidate bacteria that arebiomarkers for a metabolic disorder (e.g., type 2 diabetes and/orobesity). An effective dose of a bacterial composition from a lean donoris administered by rectal or enteric means for an effective time periodor for the duration of treatment with the gastrointestinal implant. Thebacterial composition may be administered with other agents, includinganti-microbial agents and prebiotics. The patient is recommended a dietregimen to support colonization of fecal microbes from lean donor. Thegastrointestinal implant is removed after 1 year of treatment. At theconclusion of therapy, combination of gastrointestinal implant and fecaltransplant is found to facilitate durable weight loss and comorbidityimprovement than gastrointestinal implant or fecal transplant alone.

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference. In the eventof conflicting definitions between this and any reference incorporatedherein, the definition provided herein applies.

While the disclosure has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the disclosure following, in general, theprinciples of the disclosure and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the disclosure pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

What is claimed is:
 1. A method of treating a metabolic disorder in anindividual undergoing treatment with a gastrointestinal implant, themethod comprising administering one or more metabolic agents to theindividual in an amount and for a duration to treat the metabolicdisorder.
 2. The method of claim 1, wherein the one or more metabolicagents comprises an incretin modulator.
 3. The method of claim 2,wherein the incretin modulator is a glucagon-like peptide-1 (GLP-1)receptor agonist.
 4. The method of claim 3, wherein the GLP-1 receptoragonist is liraglutide, exenatide, lixisenatide, dulaglutide, oralbiglutide.
 5. The method of claim 4, wherein the liraglutide isadministered at a dose from 0.006 mg to 3 mg.
 6. The method of claim 4,wherein the exenatide is administered at a dose from 0.05 μg to 10 μg.7. The method of claim 4, wherein the lixisenatide is administered at adose from 0.1 μg to 20 μg.
 8. The method of claim 4, wherein thedulaglutide is administered at a dose from 0.0075 mg to 1.5 mg.
 9. Themethod of claim 4, wherein the albiglutide is administered at a dosefrom 0.3 mg to 50 mg.
 10. The method of claim 2, wherein the incretinmodulator is a dipeptidyl peptidase-4 (DPP-4) inhibitor.
 11. The methodof claim 10, wherein the DPP-4 inhibitor is sitagliptin, saxagliptin,alogliptin, or linagliptin.
 12. The method of claim 11, wherein thesitagliptin is administered at a dose from 0.25 mg to 100 mg.
 13. Themethod of claim 11, wherein the saxagliptin is administered at a dosefrom 0.025 mg to 5 mg.
 14. The method of claim 11, wherein thealogliptin is administered at a dose of 0.0625 mg to 25 mg.
 15. Themethod of claim 11, wherein the linagliptin is administered at a dose of0.025 mg to 5 mg.
 16. The method of any one of claims 1 to 15, whereinthe one or more metabolic agents is administered by an enteral route.17. The method of any one of claims 1 to 15, wherein the one or moremetabolic agents is administered by a parenteral route.
 18. The methodof any one of claims 1 to 17, wherein the one or more metabolic agentsis administered one or more times per month.
 19. The method of claim 18,wherein the one or more metabolic agents is administered one or moretimes per week.
 20. The method of claim 19, wherein the one or moremetabolic agents is administered one or more times per day.
 21. Themethod of any one of claims 1 to 20, wherein the one or more metabolicagents is administered prior to treatment with the gastrointestinalimplant.
 22. The method of any one of claims 1 to 20, wherein the one ormore metabolic agents is administered during treatment with thegastrointestinal implant.
 23. A method of treating a metabolic disorderin an individual undergoing treatment with a gastrointestinal implant,the method comprising one or more bariatric procedures to treat themetabolic disorder.
 24. The method of claim 23, wherein the one or morebariatric procedures comprises a restrictive bariatric procedure. 25.The method of claim 24, wherein the restrictive bariatric procedurecomprises providing a space-occupying device to an individual.
 26. Themethod of claim 25, wherein the space-occupying device is anintragastric balloon.
 27. The method of claim 24, wherein therestrictive gastric procedure comprises a gastroplasty procedure. 28.The method of claim 27, wherein the gastroplasty procedure comprisesplacing transmural tissue anchor plications in the gastric fundus andbody.
 29. The method of any one of claims 23 to 28, wherein the one ormore bariatric procedures is administered prior to treatment with thegastrointestinal implant.
 30. The method of any one of claims 23 to 28,wherein the one or more bariatric procedures is administered duringtreatment with the gastrointestinal implant.
 31. A method of treating ametabolic disorder in an individual undergoing treatment with agastrointestinal implant, the method comprising administering one ormore microbiota modulators to an individual in an amount and for aduration to treat the metabolic disorder.
 32. The method of claim 31,wherein the one or more gastrointestinal microbiota modulators comprisestreatment with one or more species of bacteria.
 33. The method of claim32, wherein the treatment with one or more species of bacteria isprovided by a fecal microbiota transplant.
 34. The method of claims 31,wherein the one or more gastrointestinal microbiota modulators comprisesa prescribed diet regimen.
 35. The method of claim 34, wherein theprescribed diet regimen comprises a food enriched in one or morepolyphenols, saccharides, polysaccharides, peptides, polypeptides,lipids, or any combination thereof.
 36. The method of claim 34, whereinthe prescribed diet regimen comprises a food enriched in one or morespecies of bacteria.
 37. The method of claim 31, wherein the one or moregastrointestinal microbiota modulators comprises a dietary supplement.38. The method of claim 37, wherein the dietary supplement is aprebiotic supplement.
 39. The method of claim 37, wherein the dietarysupplement is a probiotic supplement.
 40. The method of claim 38,wherein the prebiotic supplement comprises a polyphenol, saccharide,polysaccharide, peptide, polypeptide, lipid, or any combination thereof.41. The method of claim 31, wherein the one or more gastrointestinalmicrobiota modulators comprises treatment with one or morebacteriophage.
 42. The method of any one of claims 31 to 41, wherein theone or more gastrointestinal microbiota modulators is administered priorto treatment the gastrointestinal implant.
 43. The method of any one ofclaims 31 to 41, wherein the one or more gastrointestinal microbiotamodulators is administered during treatment with the gastrointestinalimplant.
 44. The method of any one of claims 31 to 41, wherein the oneor more gastrointestinal microbiota modulators is administered by anenteral route.
 45. The method of any one of claims 31 to 41, wherein theone or more gastrointestinal microbiota modulators is administered by aparenteral route.
 46. The method of any one of claims 31 to 45, whereinthe one or more gastrointestinal microbiota modulators modifies thecomposition, growth, or activity of the gastrointestinal microbiota ofthe individual.
 47. The method of any one of claims 1 to 46, the methodcomprising (a) providing a gastrointestinal implant to the individual,wherein the implant comprises a sleeve, and (b) recommending: (i) one ormore bariatric procedures to treat a metabolic disorder, (ii)administration of one or more metabolic agents in an amount and for aduration to treat the metabolic disorder, or (iii) administration of oneor more microbiota modulators in an amount and for a duration to treatthe metabolic disorder.
 48. The method of any one of claims 1 to 47,wherein the metabolic disorder is type 2 diabetes, obesity,non-alcoholic steatohepatitis (NASH), or non-alcoholic fatty liverdisease (NAFLD).
 49. The method of any one of claims 1 to 48, whereinthe gastrointestinal sleeve is configured for implantation within agastrointestinal tract at or distal to a pylorus of the individual. 50.The method of any one of claims 1 to 49, wherein the gastrointestinalsleeve comprises a wave anchor.
 51. The method of claim 50, wherein thewave anchor is a barbed wave anchor.
 52. The method of claim 50 or 51,wherein the wave anchor is configured to reside distal to a pylorus ofthe individual.